This invention relates to a method of improving mucus clearance, and more particularly, the invention relates to the use of a polysaccharide such as dextran to improve mucus clearance.
Mucus is a critical component of the primary defense mechanism of the respiratory tract, trapping inhaled particulate and microbial material for removal via the mucociliary system. When this mechanism fails to clear sufficiently, mucus accumulates, and must be coughed up as sputum; otherwise it is retained in the respiratory tract, encouraging colonization by microorganisms, which may lead to chronic lung inflammation and obstruction. In cystic fibrosis (CF), airway mucus obstruction has long been considered the most insidious agent of morbidity and mortality. Therapies designed to thin the airway mucus and improve its clearability continue to be a major focus of attention.
Airway mucus is a complex, viscoelastic gel whose physical properties are important for airway defense. Mucus is a variable mixture of water, mucous glycoproteins, low molecular weight ions, proteins, and lipids. The three-dimensional structure that forms the mucous gel is dependent upon a number of forms of bonding. The main elements include the following: 1) disulfide bondsxe2x80x94these covalent links are mainly intramolecular, and join glycoprotein subunits into extended macromolecular chains known as mucins. 2) Because of their extended size, these mucin polymers readily form entanglements with neighboring macromolecules; these act as time-dependent crosslinks, which are susceptible to mechanical degradation. 3) The sugar units that make up the oligosaccharide side-chains (about 80% of the mucin weight), form hydrogen bonds with complimentary units on neighboring mucins. Although each bond is weak and readily dissociates, the numbers of bond sites make this type of bonding potentially very important. 4) Mucins are also ionized, containing both positively charged amino acid residues as well as negatively charged sugar units, principally sialic acid and sulfated residues. These increase in airway disease in general, and in CF the proportion of sulfated residues is further elevated because of alterations in glycosyl transferase activities within the Golgi apparatus. The ionic interactions between fixed negative charges result in a stiffer, more extended macromolecular conformation, effectively increasing the polymer size and adding to the numbers of entanglements. 5) Added to this in airway diseases characterized by infection and inflammation, especially CF, are the extra networks of high molecular weight DNA and actin filaments released by dying leukocytes, and exopolysaccharides secreted by bacteria.
One of the primary aspects of the current treatment of CF lung disease is aimed at changing the physical properties of pulmonary secretions to improve their clearance from the airways. The most successful therapy in CF, and the only mucoactive agent with proven efficacy, is rhDNase. Treatment with rhDNase is based on the fact that the major factor involved in the elevated viscoelasticity of CF sputum is attributed to the presence of naked DNA released into the airway surface fluid (ASF) from bacteria, neutrophils, and other cellular debris. Enzymatic digestion of these DNA macromolecules effectively decreases mucus viscoelasticity and spinnability and enhances the clearability of airway secretions. Other direct-acting mucolytic treatments, such as N-acetylcysteine derivatives, gelsolin, and hypertonic saline, are effective in vitro in CF, but may not necessarily show clinical efficacy. Indirect mucolysis, such as with inhaled amiloride, which blocks the uptake of salt and water across the airway epithelium, is a strategy aimed at enhancing the degree of hydration and diluting the macromolecular component of the ASF. Combined mucokinetic therapies may aim to address more than one mechanism involved in the control of airway mucus secretion and clearance.
DNase, gelsolin and acetylcysteine derivatives are all similar in action in that they degrade the three-dimensional network by mucolysis, or molecular weight disruption. This tends to preferentially affect the elasticity components of the network (as opposed to viscosity), which in model studies improve cough or airflow clearance more than clearance by ciliary action. Agents that affect ionic charge interactions and hydrogen bonds, on the other hand, are not true mucolytic agents because they alter the crosslink density without reducing polymer chain length, the result of which is common reduction in both elasticity and viscosity, and a preferential improvement in ciliary clearance according to model studies.
Ionic agents such as sodium chloride are believed to be mucoactive by shielding the fixed charges along the macromolecular core of the mucin polymer, making it less stiff and less extended and thus reducing the number of entanglement crosslinks with neighboring macromolecules. Wills et al (J Clin Invest 1997; 99: 9-13) disclose that the degree of crosslink reduction is related to the ionic strength in the range of 0 to 500 mOsm NaCl. Nonionic agents such as sugar have also been suggested to improve mucus clearance by increasing osmolarity. Wills et al (J Clin Invest, supra) disclose that increasing the sputum osmolarity by addition of non-electrolytes such as glucose, mannitol and urea increases the ciliary transportability. PCT publication no. WO 95/22993 published on Aug. 31, 1997 similarly discloses increasing mucociliary clearance by inhalation of a substance capable of altering the osmolarity of airway surface liquid, including sugar. On the other hand, PCT publication no. WO 95/28944 published on Nov. 2, 1995 discloses that non-ionizable material such as glucose are not effective in improving sputum transportability.
Dextran is a bacterial byproduct; the dextran macromolecule consists of end-to-end linked glucan groups. Its primary clinical uses are as a plasma volume expander and as an antithrombotic agent which has antiaggregation effects. Dextran has also been shown to exhibit antiadhesive properties in airway epithelial cells, which may make it of value as an antimicrobial agent in preventing the Pseudomonas infection in CF patients (U.S. Pat. No. 5,514,665 issued May 7, 1996 to Speert et al; Barghouthi et al Am J Respir Crit Care Med 1996; 154: 1788-1793).
It has now been found that dextran decreases mucus viscoelasticity and increases mucociliary clearability. The present invention relates to this unexpected finding that dextran and other polysaccharides may be used to improve mucus clearance.
In one aspect, this invention relates to a method of improving mucus clearance comprising administering to the respiratory tract of a patient in need of such treatment an effective amount of a polysaccharide.
In another aspect, this invention relates to a method of treating lung disease associated with impaired mucus clearance comprising administering to the respiratory tract of a patient in need of such treatment an effective amount of a polysaccharide.
In yet another aspect, this invention relates to a method of improving mucus clearability in a patient having cystic fibrosis comprising administering to the respiratory tract of said patient in need of such treatment an effective amount of dextran.
Preferably, the molecular weight of polysaccharide administered will be less than about 500,000, and more preferably less than about 250,000.